Liver failure is a syndrome caused by the incapacity of the liver to adequately perform its functions. Liver failure may be acute, e.g., caused by acute diseases such as acute viral or toxic hepatitis, or it may be chronic (Chronic Liver Failure, or “CLIF”), e.g., caused by alcoholism, hepatitis B or C, or fatty liver disease. CLIF is by far the most common presentation of liver failure, and typically is associated with cirrhosis, in which healthy liver tissue is replaced by scar tissue, and fails to adequately cleanse the blood of toxins and waste products. CLIF is typically associated with functional failure of several other organs, including the cardiovascular system, brain, kidneys, and adrenal glands, and immune defense mechanisms against endogenous and exogenous bacterial infections. In addition, patients with CLIF are susceptible to Acute on Chronic Liver Failure (AOCLIF), a complex syndrome in which an acute precipitating factor, such as infection or injury to the liver, causes the acute development of complications related to CLIF and failure in the function of other organs. The probability of survival of patients with CLIF is short, typically less than 3 years, and AOCLIF is the complication associated with the worst prognosis. Liver transplantation is therefore the treatment of choice in patients with advanced CLIF. Unfortunately, only a minority of patients may receive transplants because of the great imbalance between potential recipients and donors.
The mechanism of CLIF is complex and not related to the impairment of liver function alone, as is the case with other organ failures. Impairment of liver function is caused by the progressive destruction of liver tissue that reduces liver mass, and thus reduces the number of functional hepatocytes. The net effect of such a reduction is the impairment of synthetic and excretory function, which modifies the levels of several substances in blood and thus may detrimentally impact the function of multiple organs. Measurement of the blood concentration of these substances thus may be used as indicators of liver failure, e.g., an decrease in albumin or coagulation factors, and/or an increase in toxins such as ammonia or bilirubin. Hepatic encephalopathy may result from the accumulation of some of such toxins plus the activation of inflammatory pathways. Immune defense mechanisms may be impaired, causing an increased passage of viable bacteria and bacterial products (e.g., endotoxin) from the intestinal lumen into the systemic circulation, causing infections such as spontaneous bacterial peritonitis and/or systemic inflammatory response such as increased circulating levels of damaging cytokines. Destruction of liver mass may also activate regenerative mechanisms that promote the development of liver cancer, e.g., hepatocellular carcinoma. Liver cell necrosis also may lead to fibrosis disruption of the intrahepatic circulation and increase in hydrostatic pressure in the portal vein (referred to as portal hypertension), which may cause oesophageal varices that may rupture and manifest as gastrointestinal hemorrhage. Portal hypertension also may cause ascites, in which fluid chronically collects in the peritoneal cavity. As CLIF progresses there also may be changes in cardiovascular function, including arterial vasodilation, decrease in cardiac function, and increased release of a series of vasoconstrictor substances, such as renin and noradrenaline, that may cause renal failure secondary to renal vasoconstriction (hepatorenal syndrome) and may participate in the pathogenesis of multiorgan failure in AOCLIF.
Current therapies for CLIF have been developed for the complications associated with the syndrome, such as ascites, infections, encephalopathy, bleeding, and liver cancer. For example, hepatic encephalopathy may be treated with agents such as probiotics, antibiotics, and/or cathartics that decrease the generation of ammonia and other toxic substances in the gut and thus decrease the amount of toxins for the diseased liver to process. Treatment of circulatory dysfunction and renal failure may include administering albumin, a protein that binds to several toxins that cause vasodilations, which may improve cardiac function. Other therapies may be focused on measures that compensate for excessive fluid retention (e.g., administering diuretics to treat ascites); decrease pressure in the oesophageal varices (e.g., administering beta adrenergic blockers); eradicate the varices (e.g., banding of varices using endoscopy); kill infection-causing bacteria (e.g., administering antibiotics); and/or increase blood pressure (e.g., administering vasoconstrictors to treat circulatory dysfunction). Such approaches are reactive and predominantly directed at the active management of a patient with manifest complication(s).
Because the life expectancy of patients with CLIF is relatively short and because the availability of liver transplants is insufficient, a need has arisen to provide artificial means to cleanse the body of toxins and waste products, such as endogenous metabolites, which are known to be particularly critical in maintaining the function of the liver and other organs. Initial systems for doing so were developed in the 1970s, and were based on the traditional form of dialysis, in which a patient's blood was removed from the body, passed through a dialysis machine, and returned to the body. Although such systems showed some benefit, it was found that they were insufficiently able to remove water-insoluble, albumin-bound toxic substances. One step forward in this regard was the introduction of charcoal hemoperfusion, but biocompatibility problems limited the use of such systems.
Presently, there are two general categories of Artificial Liver Support Systems (“ALSS”), namely bioartificial and artificial livers. Both are based on connecting the patient circulatory system to an extracorporeal circuit, in which the blood or the plasma of the patient is circulated through bioreactors that contain liver cells (bioartificial) or through capillaries in columns with dialysis fluid (artificial) that may be enriched with albumin, which has a high capacity to bind water-insoluble toxic substances. Although bioartificial livers have shown to improve survival in some groups of patients, they are very complex and expensive, and have the limitation of requiring viable liver cells during the procedure.
Artificial ALSS systems, such as MARS (Molecular Adsorbent Recirculating System) and Prometheus, utilize a dialysate solution containing albumin. The MARS system is widely used. In addition to conventional dialysis, MARS provides hemodialysis against a dialysate solution that contains albumin using a membrane that is permeable to small and middle molecular weight substances. Water soluble and insoluble substances accumulated in the blood are transferred along a concentration gradient to the secondary circuit that contains the albumin dialysis solution. Those that are water insoluble are transiently bound by albumin in the secondary circuit, and subsequently by resins and charcoal absorbent columns, which regenerates the albumin for use in binding additional water insoluble substances. Water-soluble substances are removed by the conventional dialysis.
Although numerous studies of ALSS in patients with AOCLIF have shown significant beneficial effects in cardiovascular function, hepatic encephalopathy and, in patients with renal failure, in blood urea and serum creatinine levels, a substantial survival benefit has not been shown. This may be because the disease has progressed too far by the time ALSS treatment has begun. Additionally, because ALSS involves extracorporeal blood processing, it requires the use of catheters, anticoagulation medication, and close clinical control, and therefore requires hospitalization. This may significantly increase the cost of treating the patient and reduce his quality of life, thus potentially reducing compliance.
Alternative approaches have been developed for cleansing the blood of toxins and waste products based on peritoneal dialysis, in which dialysate is introduced into the patient's peritoneal cavity. For example, U.S. Pat. No. 7,169,303 to Sullivan describes passing dialysate into a patient's peritoneal cavity, then withdrawing the dialysate from the peritoneal cavity and passing the withdrawn dialysate through an extracorporeal treatment system that includes a sorbent suspension for toxin removal. Although such a method may avoid the need to withdraw blood as in ALSS, it still may be used only at too late a stage in the progression of CLIF and still may require hospitalization because of its extracorporeal nature.
U.S. Pat. No. 8,012,118 to Curtin describes a wearable dialysis system for removing uremic waste metabolites and fluid from a patient suffering from renal disease, in which a small external pump continuously recirculates peritoneal dialysis solution between the peritoneal cavity, where uremic waste metabolites diffuse through the peritoneal membrane into the dialysis solution, and a replaceable cartridge that cleans the solution and that may be replaced when the various layers become saturated. Curtin describes that albumin can be added to the peritoneal dialysis solution in the removal of protein-bound toxins and that a bacterial filter may be used to remove bacterial contamination from the solution. Curtin further describes that the fluid loop includes a replaceable drain container that drains excess fluid that has been added to the peritoneal dialysis solution through osmosis from the patient's body. A plurality of hollow fiber membranes may be connected to the patient's blood stream via vascular grafts to remove excess fluid from the blood stream, and that such excess fluid may be drained to the patient's bladder.
Although the system described in Curtin may avoid the need for frequent hospitalization and improve convenience to the patient, the dialysis is still performed extracorporeally, requires the periodic replacement of cartridges and the periodic draining of excess fluid that has been added to the peritoneal solution through osmosis from the patient's body, and is susceptible to contamination by pathogens not captured by the bacterial filter, either because the pathogens are sufficiently small or do not circulate through the filter. Moreover, as for ALSS and previously-known peritoneal dialysis, the system of Curtin may not be implemented until a patient is at a more advanced stage of CLIF and thus less likely to achieve an improved life expectancy. Further, the treating physician's involvement may be relatively infrequent because it is based on office visits, so the physician may not be aware of—nor in a position to immediately treat—a change in the patient's health.
In view of the above-noted drawbacks of previously-known systems, it would be desirable to provide methods and apparatus for treating CLIF using an implantable device having a minimum number of parts requiring replacement, avoids the need for the patient to handle multiple types of fluid, and reduces the risk of infection, allows for continual physician involvement, and that may be used at earlier stages of CLIF and thus reduce complications associated with CLIF.